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In These T Cells, HIV Does No Harm

In These T Cells, HIV Does No Harm

September 01, 1997

Researchers have identified certain T cells that suppress the reproduction
of HIV carried within them. These cells, called naive CD4 T cells, mount
the body's initial response to infections such as HIV. About half of all
CD4 T cells circulating in a healthy adult are "naive."

The finding that HIV cannot replicate in these cells-and as a result
cannot directly harm them-could lead to new weapons against HIV, said Mario
Roederer, a genetics research associate at Stanford University School of
Medicine. It also adds to the evidence that something other than viral
infection destroys HIV patients' T cells.

"Until now, many researchers believed that the CD4 T cells disappear
because HIV gets into them and kills them. But since HIV does not kill
naive T cells, something else must be causing the loss of these cells in
people with HIV disease," said Roederer, lead author of a paper describing
the finding in the April issue of the Journal of Clinical Investigation.

"Our current theory is that it's the destruction of the thymus
that is causing the abnormally low levels of T cells. But we don't really
know," he said.

The thymus is a chestnut-sized gland at the base of the throat. All
T cells originate in the bone marrow and then migrate to the thymus, where
they are "taught" to recognize foreign molecules, or antigens.
The thymus then releases the T cells into the bloodstream, where they lie
in wait to intercept invaders. Because they have not yet encountered an
antigen, these cells are called naive.

Once they meet their first foreign molecule, naive T cells initiate
an attack, proliferate and turn into specific "memory" T cells,
which protect the body against subsequent attack from the same invader.

Two types of T cells-CD4 and CD8-serve as the main actors in the immune
system's efforts to seek and destroy foreign molecules.

In 1995 Roederer and colleagues published the first report that patients
with HIV had very few naive CD8 T cells. Before that, most researchers
thought naive CD8 T cells were unaffected by HIV infection because it was
known that HIV couldn't get inside CD8 T cells.

Roederer's report, in the May 1995 Journal of Clinical Investigation,
showed that naive CD8 T cells in people with HIV were vanishing, despite
the cells' resistance to direct HIV infection. This was one of the first
inklings that something other than direct viral infection destroys the
T cells in people with HIV disease, Roederer said. The finding sparked
his curiosity about HIV's ability to replicate in different types of T
cells.

To evaluate this ability, the researchers had to trigger the T cells
to divide, since HIV replicates only minimally in quiescent cells. In test
tube studies, they separated HIV-infected naive T cells from HIV-infected
memory T cells and got them to divide by exposing them to the body's natural
stimulatory proteins.

"What was interesting was that the memory cells produced virus
under this stimulation, but the naive cells produced none," Roederer
said. "The virus did not replicate in the naive cells, although the
virus was there. The cells divided like mad, but the virus did not come
out. That's interesting because it breaks the paradigm of viral replication
being tied to cell replication. Now we know there are ways of activating
cells which do not activate virus," he continued. "It also means
naive cells in some way suppress viral replication. How? If we could figure
out how they suppress replication, that could lead to a therapy,"
Roederer said.

Support From Another Study

The new finding is bolstered by the results of another recent study
showing that HIV replication is impaired in weakly stimulated naive CD4
T cells. In this study, reported in the March issue of the journal Blood
by Tom Folks of the Centers for Disease Control and Prevention, researchers
stimulated CD4 T cells to divide using a different strategy. They got essentially
the same result as Roederer: no HIV replication.

The observation that HIV does not replicate in naive CD4 T cells explains
a surprising finding reported in the June 28, 1996, Science, Roederer
said. In that study, led by Carl June of the Naval Medical Research Institute
in Bethesda, Maryland, researchers triggered HIV-infected CD4 T cells-both
naive and memory types-to divide repeatedly, increasing in number one million-fold.

After these divisions, the researchers found no virus left in the culture.
"It's as if the culture cured itself of HIV," Roederer said.
Some researchers have suggested using this phenomenon therapeutically.

"You could take CD4 T cells from people with HIV and allow the
cells to multiply. This would eliminate the virus from their cells. Then
you could give them back their own virus-free cells," Roederer said.
His new study suggests an explanation for the disappearance of HIV from
CD4 T cell cultures that have gone through many generations of divisions.
Roederer said he suspects that the naive cells' ability to proliferate
more quickly than memory cells allowed the naive cells to take over the
final cell mixture in Carl June's study. And since HIV cannot replicate
in the naive cells, the amount of virus dwindled to nothing after repeated
cell divisions.

The research was funded in part by the National Cancer Institute and
the National Institute of Allergy and Infectious Diseases.

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